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The Effect of TLR4 Inhibition in Obese and Type 2 Diabetic Subjects (Eritoran2)

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ClinicalTrials.gov Identifier: NCT02267317
Recruitment Status : Terminated (Study drug expired)
First Posted : October 17, 2014
Last Update Posted : September 18, 2018
Sponsor:
Information provided by (Responsible Party):
Nicolas Musi, The University of Texas Health Science Center at San Antonio

Brief Summary:
To determine whether pharmacologic inhibition of Toll-like receptor 4 (TLR4) with eritoran for injection (E5564) will reduce inflammation and improve glucose metabolism in insulin resistant (obese and T2DM) subjects.

Condition or disease Intervention/treatment Phase
Insulin Sensitivity Drug: Eritoran Other: D5W Phase 2

Detailed Description:
E5564 = Eritoran

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase 2 Study of The Role of Pharmacologic Inhibition of TLR4 With E5564 on Glucose Metabolism in Insulin Resistant Subjects.
Study Start Date : January 2015
Actual Primary Completion Date : September 2018
Actual Study Completion Date : September 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Allergy

Arm Intervention/treatment
Active Comparator: Lean with normal glucose tolerance (NGT)

Lean NGT; (20 Completers) Lean = BMI less than 26 kg/m2. NGT = Normal Glucose Tolerance.

Infusion protocol: Administer eritoran for injection 12 milligrams IV every 12 hours for 72 hours (6 doses) to inhibit TLR4 or placebo

  • In the first infusion visit; each subject will receive either the Eritoran 12 mg IV every 12 hours or the vehicle (D5W) 12 mg IV every 12 hours.
  • In the second infusion visit; each subject will receive one of the remaining infusion pairings that have been randomized to them
Drug: Eritoran
Pharmacologic inhibitor of TLR4 receptors.
Other Name: E5564

Other: D5W
5% Dextrose Water = Vehicle

Active Comparator: Obese with NGT

Obese with NGT; (20 Completers) Obese = BMI 30-37 kg/m2. NGT = Normal Glucose Tolerance.

Infusion protocol;

  • In the first infusion visit; each subject will receive either the Eritoran 12 mg IV every 12 hours or the vehicle (D5W) 12 mg IV every 12 hours.
  • In the second infusion visit; each subject will receive one of the remaining infusion pairings that have been randomized to them
Drug: Eritoran
Pharmacologic inhibitor of TLR4 receptors.
Other Name: E5564

Other: D5W
5% Dextrose Water = Vehicle

Active Comparator: Obese with T2 DM

Obese with T2 DM; (20 completers) Obese = BMI 30-37 kg/m2. T2DM = Type 2 Diabetes Mellitus.

Infusion protocol;

  • In the first infusion visit; each subject will receive either the Eritoran 12 mg IV every 12 hours or the vehicle (D5W) 12 mg IV every 12 hours.
  • In the second infusion visit; each subject will receive one of the remaining infusion pairings that have been randomized to them
Drug: Eritoran
Pharmacologic inhibitor of TLR4 receptors.
Other Name: E5564

Other: D5W
5% Dextrose Water = Vehicle




Primary Outcome Measures :
  1. Effect of Eritoran on muscle insulin action [ Time Frame: within 70 days (plus or minus 10 days) ]
    Muscle insulin action = insulin signaling and peripheral glucose disposal in muscle

  2. Effect of Eritoran on hepatic insulin sensitivity [ Time Frame: within 70 days (plus or minus 10 days) ]
    Hepatic insulin sensitivity = What insulin suppression of endogenous glucose production in liver is


Secondary Outcome Measures :
  1. Effect of Eritoran on inflammatory signaling in muscle and adipose tissue [ Time Frame: within 70 days (plus or minus 10 days) ]
  2. Effect of Eritoran on TLR4 expression in peripheral blood monocytes [ Time Frame: within 70 days (plus or minus 10 days) ]
  3. Effect of Eritoran on Plasma cytokine concentration [ Time Frame: within 70 days (plus or minus 10 days) ]
  4. Effect of Eritoran on Intramyocellular diacylglycerol and ceramide content [ Time Frame: within 70 days (plus or minus 10 days) ]


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects capable of giving informed consent.
  • lean (BMI <26 kg/m2) with normal glucose-tolerant subjects without a family history of type 2 DM
  • obese (BMI 30-37 kg/m2) with normal glucose-tolerant subjects
  • Type 2 DM subjects base on ADA criteria, who have HbA1c <8.5% and control with diet or sulfonylureas.
  • Both genders. (50% males)
  • Age = 18-65 years. Older subjects are excluded because aging is a pro-inflammatory state.
  • All ethnic groups
  • Premenopausal women in the follicular phase, non-lactating, and with a negative pregnancy test. Postmenopausal women on stable dose of or not exposed to hormone replacement for >=6 months.
  • Lab: Hematocrit >=34%, serum creatinine <=1.4 mg/dL, normal electrolytes, urinalysis, and coagulation tests. Liver function tests up to 2x normal range.
  • Stable body weight (+/-1%) for >=3 months.
  • One or less sessions of strenuous exercise/wk for last 6 months.

Exclusion Criteria:

  • Current treatment with drugs known to affect glucose and lipid homeostasis. Subjects on a stable dose of statin (>3 months) are eligible.
  • Non-steroidal anti-inflammatory drugs or systemic steroid use for more than 1 week within 3 months.
  • Current treatment with anticoagulants (warfarin). Aspirin (up to 325 mg) and clopidogrel will be permitted if these can be held for seven days prior to the biopsies.
  • History of heart disease (New York Heart Classification greater than class II; more than non-specific ST-T wave changes on the ECG), peripheral vascular disease, pulmonary disease, smokers.
  • Poorly controlled blood pressure (systolic BP>160, diastolic BP>90 mmHg).
  • Active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignant, and psychiatric disease.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02267317


Locations
United States, Texas
Audie L. Murphy VA Hospital, STVHCS
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Nicolas Musi
Investigators
Principal Investigator: Nicolas Musi, MD Audie L. Murphy VA Hospital, STVHCS San Antonio, Texas, United States 78229

Responsible Party: Nicolas Musi, Professor, The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT02267317     History of Changes
Other Study ID Numbers: HSC20140498H
First Posted: October 17, 2014    Key Record Dates
Last Update Posted: September 18, 2018
Last Verified: September 2018

Keywords provided by Nicolas Musi, The University of Texas Health Science Center at San Antonio:
Insulin signaling and glucose disposal in muscle
Hepatic insulin sensitivity
TLR4 signaling and inflammatory gene expression
Plasma cytokine concentration
Intramyocellular diacylglycerol and ceramide content

Additional relevant MeSH terms:
Hypersensitivity
Insulin Resistance
Immune System Diseases
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs